Abstract

Epithelial ovarian cancer (EOC) has the one of the lowest survival rates, partly due to modern therapy’s failure to consider the heterogeneity of EOC and the failure to effectively target cancer stem cells (CSC). CSCs lead to cancer relapse and metastasis. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. We aimed to determine the mechanism of epithelialmesenchymal transition (EMT)-induced stemness in cancer cells. The central hypothesis for this study is that SNAI1 directly represses let-7, leading to increased stemness in cancer cells; and that targeting SNAI1 in EOC subtypes will yield a significant improvement in terms of chemoresistance and stemness. The long-term objective is to develop effective treatment strategies for targeting cancer stem cells. The short-term goal is to utilize SNAI1 as a potential target to prevent ovarian cancer tumor growth and metastasis in a xenograft model. The hypothesis was tested through the following two specific aims: 1). Evaluate the influence of SNAI1 on let-7 and its downstream effect on stemness in cancer cells. 2). Evaluate in vitro and in vivo efficacy of targeting SNAI1 in high stemness subtypes among our patient-derived samples. To achieve these aims, we 1.1 established the relationship between expression of SNAI1, loss of let-7 and changes in stemness using Snail gain-and loss-of-function experiments in vitro and in vivo; 1.2 investigated SNAI1’s action and its direct binding to the promoter regions of let-7; 2.1 categorized our patient-derived cells into distinct EOC subtypes based on their EMT gene expression, 2.2 used SNAI1 loss-of-function experiments in vitro and in vivo to determine effect of SNAI1 on stemness in EOC subtype-specific tumors. This study showed SNAI1’s direct repression on let-7, leading to an upregulation of cell stemness. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.

LLU Discipline

Physiology

Department

Physiology

School

School of Medicine

First Advisor

Juli Unternaehrer

Second Advisor

Carlotta Glackin

Third Advisor

Eileen Brantley

Fourth Advisor

Penelope J. Duerksen-Hughes

Fifth Advisor

Ubaldo Soto

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2021

Date (Title Page)

5-2021

Language

English

Library of Congress/MESH Subject Headings

Carcinoma, Ovarian Epithelial; Neoplastic Stem Cells; Epithelial-Mesenchymal Transition; Snail Family Transcription Factors

Type

Dissertation

Page Count

xxi, 220 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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